Open access peer-reviewed chapter

The Angiogenic Paracrine Potential of Mesenchymal Stem Cells

Written By

Jafar Rezaie, Morteza Heidarzadeh, Mehdi Hassanpour, Hassan Amini, Elhameh Shokrollahi, Mahdi Ahmadi and Reza Rahbarghazi

Submitted: 20 November 2018 Reviewed: 15 January 2019 Published: 23 September 2019

DOI: 10.5772/intechopen.84433

From the Edited Volume

Update on Mesenchymal and Induced Pluripotent Stem Cells

Edited by Khalid Ahmed Al-Anazi

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Abstract

Tissue engineering and regenerative medicine are branches of biomedical sciences that facilitate the use of cells and biocompatible scaffolds in favor of tissue restoration. In this regard, restoration and maintenance of angiogenesis and blood supplementation could be an effective strategy for injured tissue removal, accelerating healing rate, and successful transplantation of cells and scaffolds into target sites. It has been elucidated that mesenchymal stem cells have the potency to promote angiogenesis via paracrine activity and trans-differentiation into the endothelial lineage. In this chapter, we highlighted the paracrine property of mesenchymal stem cells to modulate angiogenesis in the target tissues.

Keywords

  • mesenchymal stem cells
  • angiogenesis
  • paracrine activity
  • exosomes

1. Introduction

Angiogenesis, termed as neovascularization, is defined as de novo vascularization from the pre-existing vascular network and activated in response to numerous pathological and physiological stimuli, playing critical roles during development and tissue repair [1]. Recent advances in the field of stem cell research, notably MSCs, have opened new horizons to human medicine in the promotion of angiogenesis and restoration and salvage of ischemic tissues [2]. MSCs actively participate in angiogenesis via direct differentiation, cell contact interaction with endothelial lineage, and releasing pro-angiogenic factors via a paracrine manner [3]. Due to the low survival and differentiation rate of MSCs posttransplantation into ischemic microenvironment, it is proposed that the paracrine activity is the principal mechanism for the therapeutic outcome [4]. It has been well-established that stem cell-secreted growth factors are responsible for, at least in part, therapeutic effects. As a matter of fact, MSC-derived secretome is thought to be a suitable alternative therapeutic modality to MSCs posttransplantation. At present, the underlying mechanisms by which MSC secretomes contribute to tissue healing and angiogenesis are not fully addressed and many efforts are needed to fill knowledge gaps by experimental animal research and clinical trials prior to application to human medicine [5, 6]. Paracrine factors could increase the blood supplement of damaged tissues via the activation and recruitment of resident/circulating stem cells and progenitor cells [7, 8]. Several experiments detected the pro-angiogenic capacity of MSCs isolated from different sources [9, 10]. Table 1 ELISA and liquid-chip assays of cytokine content of umbilical cord MSCs revealed several angiogenesis factors, including interleukin-8 (IL-8), insulin-like growth factor 1 (IGF-1), and vascular endothelial growth factor (VEGF) compared to mature cell types such as fibroblasts. These pro-angiogenic factors are able to form vascular networks and increase the migration of endothelial lineage in vitro [51]. In addition to the secretion of angiogenic factors by MSCs, it was revealed that various factors existing in secretome could activate the angiogenic behavior in endothelial cells (ECs). For instance, equine peripheral blood MSC angiocrine was found to stimulate endothelial functional behavior by the induction of VEGF-A signaling pathway via several factors such as endothelin-1, IL-8, platelet-derived growth factor-AA (PDGF-AA), and IGF-2 [52]. Due to the variety of factors released by MSCs such as VEGF, monocyte chemoattractant protein-1 (MCP-1), and IL-6, an increased angiogenesis rate was observed in the mouse model of hindlimb ischemia, and even the combination of VEGF, MCP-1, and IL-6 could be served as a commercial cocktail for the promotion of angiogenesis either in vivo or in vitro [53]. In addition to the existence of the pro-angiogenic factor in MSC secretome, some authorities, however, showed the anti-angiogenic properties of these cells (Table 2) [67]. In some circumstances, the dual effect of a distinct factor was proved related to angiogenesis status. For example, in VEGF-free condition, the attachment of angiopoietin-2 (Ang-2) to receptor tyrosine kinase (RTK), namely Tie-2, promotes vascular destabilization and regression by reduction of pericyte-EC interaction, while in normal condition Ang-2 could increase EC migration and tip cell formation required for neovascularization [68]. Commensurate with these comments, one could hypothesize that the dynamic balance of MSC secretome, cell source, purity, and preconditioning could predetermine the pro- and/or anti-angiogenic property of MSCs [67].

FactorAmniotic fluid/bone marrow MSCsFunction
Angiogenin+/+A pancreatic ribonuclease, known as ribonuclease 5, which induces vascularization [11]
Angiopoietin-1+/+Activates TEK/TIE2 receptor; promotes angiogenic processes, endothelial cell survival, migration, proliferation, and stabilization; and during embryogenesis has a role in heart development [12]
Angiopoietin-2+/−Binds to TEK/TIE2, in the presence of VEGF and Ang-2 and promotes neovascularization [13, 14]
Angiopoietin-4+/+Binds to TEK/TIE2, modulating ANGPT1 signaling, can induce tyrosine phosphorylation of TEK/TIE2, and promotes endothelial cell survival, migration, and angiogenesis [15]
Amphiregulin+/−An EGF-like ligand that binds to the EGFR, enhanced lymphangiogenesis, and stimulates the growth of normal epithelial cells [16]
Artemin+/−Binds for the GFR-alpha-3-RET and GFR-alpha-1-RET receptor and promotes angiogenesis [17]
Tissue factor+/−Stimulates PDGF receptor signaling pathway, angiogenesis, endothelial cell migration, chemotaxis and proliferation, and coagulation factor III/CD142; improves transcription of VEGF; and reduces transcription of the thrombospondins [18]
CXCL16+/+Encourages a chemotactic response, pro-angiogenic [19]
DPPIV+/−A membrane-bound oligopeptidase acting on and modulating the pro-angiogenic chemokine CXCL12 [20]
Epidermal growth factor+/−Encourages the growth of epithelial tissues, is anti-apoptotic, induces lymphangiogenesis, and improves MSC survival [21]
EG-VEGF+/−Also called Prokineticin 1. Binds to PROKR1 and PROKR2, pro-angiogenic [22]
Endothelin-1+/+Derived from the endothelium with vasoconstrictor and angiogenic effects, prolymphoangiogenic [23]
Endoglin+/−Also called CD 105. Modulates TGF-β1 and β3 responses, vascular development, and angiogenic effects [24]
FGF-7+/+Has positive effects on cell proliferation, migration and division, chemotaxis, and arteriogenesis [25]
Acidic FGF/FGF-1+/−Binds to for FGFR1 and integrins and induces angiogenesis [26]
Basic FGF/FGF-2+/−Ligand for FGFR1, FGFR2, FGFR3, and FGFR4, Vascular regeneration; role in cell migration and proliferation involved in angiogenesis, stimulates arteriogenesis [27]
FGF-4+/−Has positive effects in MSC proliferation, pro-angiogenic [28]
GDNF+/−Has positive effects in angiogenesis [29]
GM-CSF+/−Has positive effects in angiogenesis [30]
Heparanase+/+Has positive effects in angiogenesis [31]
Heparin binding-EGF+/+Has positive effects in angiogenesis [32]
Hepatocyte growth factor+/−Has positive effects in angiogenesis [33]
HIF-1α+/+Functions as a master transcriptional regulator of the adaptive response to hypoxia and influences cell metabolism, cell survival, and angiogenesis [34]
IL-1β+/−Has positive effects in angiogenesis and lymphangiogenesis [35]
IL-6+/−A potent pro-angiogenic cytokine which stimulates endothelial cell and smooth muscle cell proliferation and migration and promotes neovascularization [36]
IL-8+/−Has a role of pro-angiogenic factor [37]
Leptin+/−Stimulates vessel formation [38]
MCP-1+/−CCL2. Induces stabilization of new vessels [39]
MIP-1α+/−CCL3. Induces vessel formation
MMP-8+/−Known as collagenase 2. Breaks collagen types I, II, and III and has positive effects on angiogenesis [40]
MMP-9+/−Called as gelatinase B. Breaks both collagens and gelatins and has positive effects on angiogenesis [41]
NRG1-β1+/−Promotes angiogenesis and arteriogenesis [42]
Pentraxin-3 (PTX3)+/+Has a role of a pro-angiogenic agent [43]
PD-ECGF+/−Stimulates angiogenesis [44]
PDGF-AA+/+Has positive effects on MSC proliferation and stimulates angiogenesis [45]
PDGF-AB/PDGF-BB+/−Induces neovascularization and arteriogenesis [27]
Persefin+/−Induces angiogenesis [3]
PlGF+/+Has a role of a pro-angiogenic factor [46]
Prolactin+/−Has a role of a pro-angiogenic factor in intact form [47]
Sphingosine kinase 1+/+Promotes angiogenesis [48]
SDF-1α-/+An important chemotactic factor for progenitor cells. Stimulates stem cell migration, adhesion, and homing [3]
TGF-β1+/−Promotes angiogenesis at least in part via the secretion of the survival factors TGF-α and VEGF [3]
uPA+/+Promotes endothelial cell proliferation and migration and has positive effects in vascular network formation [49]
VEGF+/+Promotes angiogenesis [50]
VEGF-C+/−Promotes lymphangiogenesis [50]

Table 1.

Comparison of angiogenic paracrine factors secreted by MSCs from amniotic fluid and bone marrow.

FactorAmniotic fluid/bone marrow (MSCs)Function
Angiopoietin-2+/−Binds to TEK/TIE2 and induces endothelial cell apoptosis in the absence of VEGF [54, 55]
Angiostatin+/−Angiogenic inhibitor. Acts as an inhibitor of endothelial cell proliferation and migration [56]
Endostatin+/−Acts as inhibitor of endothelial cell proliferation and migration and angiogenesis and induces endothelial apoptosis [56]
TGF-β1+/−Angiogenic inhibitor [57]
Platelet factor 4 (PF4)+/−Angiogenic inhibitor [58]
Serpin B5+/−Maspin. A member of the serine protease inhibitor family and negative regulator of angiogenesis [59]
Serpin E1+/+Serine protease inhibitor; inhibition of angiogenesis; inhibitor of uPA; preserves the vascular integrity [60]
Serpin F1+/+Serine protease inhibitor, inhibition of angiogenesis [61]
TIMP-1+/+Angiogenesis inhibitor [62]
TIMP-4+/+Angiogenesis inhibitor [63]
Thrombospondin-1+/+Anti-angiogenic. Inhibits endothelial cell proliferation [64]
Thrombospondin-2+/−Anti-angiogenic. Inhibits endothelial cell migration and tubule formation [65]
Vasohibin+/−A negative feedback regulator of angiogenesis [66]

Table 2.

Comparison of anti-angiogenic paracrine factors secreted by MSCs from the amniotic fluid and bone marrow.

By modulating distinct signaling pathway/s inside the MSCs, cell bioactivity would be induced in favor of neovascularization. For instance, it was shown that the activation of sonic hedgehog (Shh) factor in Wharton’s jelly-derived MSCs (WJ-MSCs) induced the production of pro-angiogenic factors such as angiogenin, angiopoietin-1, activin A, matrix metallopeptidase-9 (MMP-9), granulocyte-macrophage colony-stimulating factor, and urokinase-type plasminogen activator, indicating WJ-MSCs an ideal cell source for the induction of vascularization [69]. An experiment conducted by Matluobi et al. showed an enhanced vascular formation capacity of human MSCs after treatment with carvacrol evaluated by chicken chorioallantoic membrane angiogenesis assay. The carvacrol-treated MSCs tended to trans-differentiate into endothelial lineage by the expression of VWF and VE-cadherin [70]. MSCs have the ability to adapt themselves with environmental condition increasing regenerative potential in different conditions [71]. Maintaining the MSC cross talk with other cells is required for cell hemostasis, stemness feature, and regenerative potential in the distinct niche. For example, the normal bioactivity of Hox gene, Abdominal-B, seems to be essential in Drosophila cystic stem cells to obtain multipotentiality [72].

Regarding issues related to isolation protocols and stem cell proliferation rate, a careful selection is essential for high-throughput results. Vizoso et al. demonstrated large-scale secretome production and release of a vast array of bioactive factors in human uterine cervical stem cells with considerable advantages over MSCs from other tissues for research and clinical application [73].

The emergence of some conditions could change the trans-differentiation capacity of MSCs into distinct phenotypes. In the case of the vicious cycle of abnormal placental development in intrauterine growth restriction, placental mesenchymal stromal cells lose angiogenic potential while acquiring adipogenic capacity which is coincided with a metabolic shift from aerobic to anaerobic state [71]. It seems that external environmental influence could alter the therapeutic potency of MSCs by rendering epigenetic marks associated with cell differentiation capacity [74]. In support of this claim, Rezaie and co-workers found a decrease of angiogenic human MSC potential after exposure to diabetic sera. The diabetic MSCs showed a declined migration capacity by suppressing the transcription of MMP-2, MMP-9, and CXCR-4 and aborted the secretion of Ang-1, Ang-2, and VEGF [75]. The expression of CXC chemokine receptors such as CXCR-1, CXCR-2, and CXCR-4 was found to accelerate and direct MSC migration in response to the chemokine gradients. A blockade of CXCR chemokine such as CXCL6 had potential to abrogate cardiac stem cell migration and motility [76].

At present, the combination of cell and tissue engineering techniques increased the restoration potential of a distinct cell type after transplantation [77]. In most of these approaches, the maintenance of cell-to-cell interaction in 3D microenvironment could increase survival signaling pathway and organotypic plasticity of cells. For instance, it seems that cell encapsulation by the mixture of alginate-gelatin promotes angiocrine cues and vascular network formation [77]. The introduction of MSC-alginate microbeads to ischemic hindlimb mouse model promoted arterial collaterals after the occlusion of the femoral artery by the modulation of VEGF-A signaling pathway [78]. A side-by-side comparison of MSCs expanded in 2D, and alginate microbeads revealed enhanced angiogenic and chemotactic activity in cutaneous healing [79].

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2. Modulation of angiogenesis by exosomes

Regarding paracrine activity, MSC exosomes transfer various bioactive molecules, microRNAs, and protein factors with the ability to modulate angiogenesis behavior in the target cells.

2.1 Exosomes biogenesis

Exosomes are a subtype of extracellular vesicles (EVs, 40–200 nm) found in bio-fluids and released from all cell types. They maintain cell-to-cell communication through shuttling diverse biomolecules [80, 81, 82]. The first intracellular step in exosome biogenesis involves the invagination of the membrane of the multivesicular body (MVB) to form membrane-bound vesicles in MVB lumens that are identified as intraluminal vesicles (ILVs) (Figure 1) [83, 84]. Various factors and signaling pathways have been considered in biogenesis, trafficking, and abscission of exosomes [85]. Of note, endosomal sorting complexes required for transport (ESCRT) machinery with four complexes, ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III, participate in exosome formation and packing cargo incorporation with different accessory proteins (Figure 1) [81, 85, 86]. Noteworthy, the formation of MVBs in the absence of the ESCRT machinery is aborted. In this condition, oligodendroglial cell ceramide is a key molecule to induce inward budding of the limiting membrane of MVBs [83, 87]. After MVB formation, intracellular trafficking of vesicle systems was orchestrated by Rab-GTPase family proteins [81]. As shown in Figure 1, several Rab proteins specifically contribute to the transfer of vesicles in definitive pathways. Along with these factors, soluble NSF attachment protein receptor (SNARE) has been suggested to control the fusion of MVBs with the plasma membrane (Figure 1) [88]. At the intracellular level, three possible fates are considered to involve MVBs such as secretory, lysosomal, and back fusion pathways. Once secreted, exosomes can be received by neighboring cells by three possible mechanisms: (i) internalization, (ii) direct fusion, and (iii) receptor-ligand interaction. Exosomal uptake results in triggering signaling pathways reprogramming fate, proliferation, survival, and morphology of recipient cells (Figure 1) [89, 90].

Figure 1.

Biogenesis, structure, and uptake of exosomes. Exosomes are producing during invagination process of MVB’s membrane. ESCRT machinery and ESCRT-independent mechanisms (lipid rafts/tetraspanin) contribute to form exosomes and sort several molecules including proteins, miRNA, mRNA, DNA strands, and lipids into their lumen or limiting membrane of exosomes. Exosome cargoes are collected from materials received by endocytic pathway, Golgi apparatus, and cytoplasm. Rab-GTPase family proteins regulate intercellular trafficking and docking of MVBs. In the secretory pathway, MVBs actively fuse with the plasma membrane to release exosomes into the extracellular space. In alternative pathways, MVB could prefer binding to the lysosome or directly fuse back to the plasma membrane. Once secreted, exosomes enroll several mechanisms to arrive at the target cell: (I) enter through internalization process; (II) bind through receptor-ligand interactions, (III) direct fusion with the plasma membrane of the target cell. Exosomes are able to affect the biological processes of the target cells.

2.2 Pro- and anti-angiogenic capacity of exosomes

It was shown that a significant portion of MSC angio-activity drives from their potency to release exosomes that can affect the function of ECs, either by increasing the production of pro-angiogenic factors or decreasing the production of anti-angiogenic factors [91]. The fact that MSC exosomes promote angiogenesis, by delivering mediators such as miRNAs, protein factors to distinct cells, was confirmed in various in vivo experimental studies [89, 92, 93].

2.2.1 miRNAs

It seems that exosomal cargo such as cytokines and miRNAs could be easily transferred to recipient cells. Increasing evidence indicates that exosomal pro-angiogenic miRNAs (miRNA-125a, miRNA-30b, miRNA-30c, miRNA-424, miRNA-150, and let-7f) are important regulators of angiogenesis in the target sites [89, 94, 95, 96]. Data suggest that exosomal miR-150 is a key contributor to the pro-angiogenic activity of MSC exosomes following ischemic injuries [89, 96, 97]. In contrast, anti-angiogenic function on tumor cells was reported by a research group guided by Lee et al. They demonstrated the anti-angiogenic function of MSC exosomes on breast cancer cells governed by delivering miR-16 to suppress VEGF factor [91]. In a recent study conducted by Chen et al., they declared that exosome can be used as therapeutic transfer vesicles to carry miRNAs and genetic molecules to modulate VEGF content and control untamed angiogenesis in rheumatoid arthritis [98]. Based on the literature, the expression of VEGF, endothelial marker CD31, and matrix metalloproteinases-14 (MMP-14) activity is induced in patients with rheumatoid arthritis. The application of MSC-derived exosomes containing miRNA-150-5p (Exo-150) clearly decreased transcription of VEGF and MMP-14 in synovial fluid. Consistent with these changes, the pro-inflammatory response was blunted by decreasing IL-1β, transforming growth factor-β (TGF-β) and tumor necrosis factor-α (TNF-α) content in synovial fluid. This study has shown that MSC-derived Exo-150 can be used as bio-shuttle and magic bullet for inhibiting an exacerbated angiogenesis via the modulation of angiogenesis-related factors. However, some contradictory facts exist regarding the sole application of exosomes in the context of tumor cells.

2.2.2 Exosomal pro- and anti-angiogenic factors

MSCs can secret signal transducer and activator of transcription-3 (STAT3) mRNAs via exosomes that augment the transcription of hepatocyte growth factor (HGF), IL-6, and VEGF, promoting proliferation and migration of ECs [99]. In this context, MSC exosomes abundantly are enriched with VEGF factor that increases neovascularization through the Wnt4/β-catenin pathway in epithelial cells [100101]. The pro-angiogenic propriety of MSC exosomes has been previously shown in myocardial ischemia/reperfusion injury experiments following acute myocardial infarction [102, 103, 104]. In contrast, MSC exosomes may contain abundant anti-angiogenic factors that could regulate tumor angiogenesis rate. Lee et al. showed that exosomes from MSCs significantly downregulated the expression of VEGF in breast cancer cells, leading to the abortion of angiogenesis [91]. However, there are contradicting results. For example, human bone marrow MSC exosomes promoted VEGF synthesis in colonic and gastric carcinomas through the activation of extracellular signal-regulated kinase1/kinase2 (ERK1/ERK2) and p38 MAPK pathways [105]. Taken together, these issues show a fact that exosomes from various MSC types can mediate physiological and pathological angiogenesis and could be considered as a suitable bio-shuttle for establishing promising therapeutic approaches in an individual with cancers and ischemic pathologies. The feasibility of exosome uptake by recipient cells, make these cell products for introducing in clinical approaches. Xue and colleagues investigated the effects of cord blood and adipose-derived MSC exosomes on human EC angiogenesis capacity under hypoxic and normal conditions [106, 107]. They noted the potency of isolated exosomes in triggering angiogenesis rate especially under the hypoxic condition compared to exosome counterpart originated from normal milieu. Based on their data, the transcription level of genes related to angiogenesis such as angiopoietin-1 (Ang-1) and VEGF receptor-2 (also termed FLK-1) was induced significantly after exposure to exosomes collected from hypoxic MSCs rather than that of normal cells. Following the induction of Ang-1 and FLK-1, the status of some downstream effectors would be turned to an activated form. For instance, it was found that protein kinase A (PKA) is indirectly triggered after the activation of genes Ang-1 and VEGFR-2. Along with changes, the transcription level of angiogenesis inhibitory gene like Vash1 is completely suppressed. The inhibitory angiogenesis potential of MSCs was investigated on cancer cells or progenitors residing inside tumor mass. Both anti-inflammatory and pro-angiogenesis property of MSC-derived exosomes were shown in cardiovascular disease [92, 97]. In addition to the promotion of cell surface receptors, exosomes could augment the synthesis of VEGF factor in targeted cells. Doeppner et al. also previously demonstrated that MSC-derived exosomes initiated healing processes after the onset of neurological diseases by increasing angiogenesis and blood supply which led to the neurological recovery and neurogenesis [108]. Other experiments added notion on the potency of exosomes to reduce neuroinflammation in traumatic brain injury [109]. However, some contradictory facts exist regarding the sole application of exosomes in the context of tumor cells. The superior stimulatory effect of MSC-derived exosomes on tumor angiogenesis was also addressed by different authors [110]. For example, Zhu et al. demonstrated the vasculogenic role of MSC exosomes after addition to human gastric carcinoma (SGC-7901) and colon cancer (SW480) cell lines [105, 111]. They found that the normal status of signaling effectors such as phosphorylated ERK1/ERK2, Bcl-2, and VEGF proteins; alpha-smooth muscle actin (α-SMA); CXCR-4; and mouse double minute 2 homolog (MDM2) mRNA was modulated in the favor of angiogenesis in a mouse cancer model. In addition to the direct fast action on recipient cells, it is reasonable to hypothesize that exosomes are able to dictate pro-/anti-angiogenesis pattern in distinct cells by provoking specific signaling pathways and effectors such as ERK1/ERK2 and p38 MAPK kinase routes.

The engagement of factors such as AKT, STAT3, Wnt/β-catenin, and ERK happens following cutaneous wound regeneration treated with MSC exosomes. Proteomic analysis revealed that the protein content of growth factors IL-6, stromal cell-derived factor-1α (SDF-1α), IGF-1α, STAT3, and HGF contributed to cell proliferation, migration, and angiogenesis, improving reepithelialization in wound sites [112]. The modulation of Wnt/β-catenin pathway targeting Wnt4 diminishes the number of cells with apoptotic changes with the levels of pro-angiogenic factors such as IL-6 and IL-8, granulocyte-colony-stimulating factor (G-CSF), PDGF-BB, MCP-1, and VEGF are increased. In response to treatment with exosomes, phosphorylation of glycogen synthase kinase 3β (GSK3β) as a main negative regulator of Wnt signaling pathway is initiated, resulting in the progression of a cell from phase G1 to S and cutaneous cell proliferation [113]. An enhanced angiogenesis rate with reduced cardiomyocyte apoptosis was reported following the administration of MSCs to infarct area. After being exposed to the ischemic/hypoxic condition, MSCs were programmed to secrete exosomes. Under these conditions, GATA-4 is induced which prevents cell apoptosis, reducing the infarct size. Meanwhile, the level of an anti-apoptotic agent such as miR-19a and miR-22 was increased in the target sites [114]. In another experiment conducted by Teng et al., it was shown that MSC-derived exosomes harboring miRNA-132 efficiently are delivered to human umbilical vein ECs (HUVECs). Therefore, it could be pointed out that MSCs could dictate prominent changes in the target cells. They also declared that endothelial Ras signaling pathway effectors are modulated by recipient cells after direct interaction of this miRNA with RASA1 gene. Ras group genes have a basic role in controlling cell proliferation and differentiation [107]. Along with these statements, the bona fide effects of MSC exosomes need to be precisely addressed by a plethora of various experiments.

In the context of tumor niche, both anti- and pro-tumorigenic features was found after the treatment of cancer cells with MSCs exosomes. The migration and proliferation of tumor cells were tightly regulated by exosome factors by the modulation of PDGFR, C-Met, and EGFR signaling. Ex vivo modulation showed this fact that MSC exosomes could activate or phosphorylate intracellular kinase domain of relevant receptors, thereby triggering Akt, PKC/PKB, and MAP signaling pathways, leading to proliferation and migration of gastric tumor cells [115]. Exosomes released by human bone marrow MSCs augmented VEGF in colonic carcinoma and gastric carcinoma tumor cells through the activation of ERK1/ERK2 and p38 MAPK pathways [105]. This hypocrisy generates doubts on the definite therapeutic effect of exosomes from MSC source in various niches. In an experiment, the lack of cell response was approved in dormant-like tumor-initiating cells [116]. The differences in tumor cells to MSC secretome may relate to the divergence of factors and dynamic growth of target cells inside tumor niche [116]. In light of various genetic and proteomic reservoir, the target signaling and possible side effects of exosome treatment are required to be investigated in relation to specific distinct signaling pathway. It seems that exosome therapy is at the beginning step, and the type and source of cells have a superior role in the orientation of target cell behavior. A more deep understanding of the regulatory signaling pathways and precise inquiry in profiling of components transferred by exosomes is required to enroll and engineer the exosomes for therapeutic angiogenesis or targeted therapy

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3. The application of MSCs and secretome in ischemic cardiac disease

Cardiovascular diseases remain the leading cause of mortality and morbidity in worldwide. Various investigators have continued to assess a large number of cell types injected through several routes to promote cardiac repair in patients with cardiovascular diseases in both the preclinical and clinical stages. Clinical studies have largely been focused on the administration of MSCs [117, 118]. For instance, intracoronary injection of bone marrow MSCs led to an improved function of the left ventricle in subjects with acute myocardial infarction [119]. Mechanisms of action of MSCs administrated to the injured myocardium include accelerating angiogenesis process, diminished fibrosis, and regulation of immune response [102120]. Both in vitro and in vivo investigations have confirmed the trans-differentiating capacity of MSCs to effective cardiomyocytes in injured cardiac tissue [50]. In addition, documents revealed that MSCs from different sources release greater amounts of angiogenic factors (HGF, VEGF, and other growth factors), cell migration chemokine (SDF-1α), immune-signaling elements (IL-6, IL-8, and MCP-1) TGF-β, neurotrophic factors (brain-derived neurotrophic factor (BDNF)), nitric oxide (NO), and improved cardiac restoration after injury [121].

Exosomes from MSCs exposed to hypoxia and FBS-free condition enhanced neovascularization in the injured heart [92, 122, 123, 124]. In a preclinical study, intramyocardial transplantation of exosome secreted from MSCs significantly improves blood flow rate and reduced infarct zone in the rat model [125]. Approximately, the entire small and large animal model of CVD preclinical investigations along with high-quality phase 0, I, II, and III clinical trials and meta-analysis studies vigorously confirmed that MSC therapy has the effective effects in developing angiogenic networks in ischemic regions [126, 127].

Ongoing researches on preconditioning and genetic manipulations of MSCs are needed to enhance angiocrine capacity governed by growth factors, microvesicles, microRNAs, long noncoding RNAs (lncRNAs), etc. [128, 129]. Finding the route of cell delivery, the optimum dose, the excellent cell source, and transplantation time are factors that still require to be addressed so as to achieve the aim of comprehensive cardiac regeneration.

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4. Angiogenesis assays

Both in vitro and in vivo angiogenesis assays are commonly used to investigate pro- and anti-angiogenic potential of stem cells and different cell types.

4.1 In vitro analyses

4.1.1 Proliferation and survival assays

Monitoring the proliferation of ECs is needed to develop microvascular units. Different survival and proliferation assays based on DNA synthesis or metabolic status are applicable. These assays could also predetermine the anti-angiogenic property of a specific compound in the context of tumor biology.

4.1.2 Migration assays

This method shows the migration in response to diverse factors, ability to digest basal membrane, and healing capacity of MSCs which is done by various assays as follows: Boyden chamber assay, Transwell® inserts, agarose assay, wound-healing assay, Teflon fence assay, phagokinetic track, etc. [130].

4.1.3 Tube formation (tubulogenesis) assay

This system is done in the 2D and 3D milieu and able to monitor alignment and juxtacrine connection of cells after plating on a specific substrate such as Matrigel, Fibrin, etc. Plated cells acquire phenotype to form capillary-like structures and lumen which are applicable to in vivo condition and evaluated in terms of tube area and number per microscopic field [130, 131].

4.1.4 Aortic ring assay

In this assay, the aorta from mouse or rats was removed and placed on collagen or fibrin matrix in serum-free condition. The angiogenic potential is determined by EC sprouting, polarized cells, and outgrowth appearance to the periphery [132].

4.2 In vivo analyses

4.2.1 Corneal angiogenesis assay

The cornea is considered as avascular tissue with unique properties for monitoring the angiogenesis and done in the model of mouse, rat, and rabbit. In the procedure of corneal angiogenesis, the candidate biomaterials and polymer with putative pro- and anti-angiogenic factors were transplanted into the stromal pouch created by surgical approach. The penetration and ingrowth of nascent vessels into the avascular area is monitored by the time [133].

4.2.2 Chicken chorioallantoic membrane angiogenesis assay

This assay is performed on embryonated eggs by using polymer pellets and silastic rings containing target molecules on the surface of the chorioallantoic membrane. After the completion of distinct time, the number and dilation of blood vessels from avian source to the implants were quantified [70].

4.2.3 Matrigel plug assay

It is a choice of in vivo angiogenesis assay following administration of gelatinous protein mixture termed Matrigel into subcutaneous space. The target molecules could be administrated with Matrigel at the site of injection and systemically to the circulation system. To precisely elucidate the formation of de novo capillaries, fluorochrome agent could be administrated into the systemic circulation [130].

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5. Conclusion

It is anticipated that MSC secretome and angiocrine could be used as an off-the-shelf alternative therapy to modulate angiogenesis/vascularization in distinct tissues. Considering both pro- and anti-angiogenic capacity, a big question remains to the identification of safety and efficacy of MSC secretome under specific conditions. Based on the data from different experiments, the angiogenic paracrine potential of MSCs is currently under investigation, and results of preclinical and translational studies, if confirmatory of previous basic experiments, could lead to human medicine for angiogenic modulation of tissues. The discovery of the signaling pathways that mastermind the paracrine pro- and anti-angiogenic potential of MSCs enables us to find appropriate policies for modulating angiogenic switch on/off in in vivo condition.

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Acknowledgments

All authors declared that there is no conflict of interest regarding the content of the current chapter.

References

  1. 1. Ucuzian AA, Gassman AA, East AT, Greisler HP. Molecular mediators of angiogenesis. Journal of Burn Care & Research. 2010;31(1):158-175
  2. 2. Hou L, Kim JJ, Woo YJ, Huang NF. Stem cell-based therapies to promote angiogenesis in ischemic cardiovascular disease. American Journal of Physiology-Heart and Circulatory Physiology. 2015;310(4):H455-HH65
  3. 3. Watt SM, Gullo F, van der Garde M, Markeson D, Camicia R, Khoo CP, et al. The angiogenic properties of mesenchymal stem/stromal cells and their therapeutic potential. British Medical Bulletin. 2013;108(1):25-53
  4. 4. Ahmadi M, Rahbarghazi R, Aslani MR, Shahbazfar AA, Kazemi M, Keyhanmanesh R. Bone marrow mesenchymal stem cells and their conditioned media could potentially ameliorate ovalbumin-induced asthmatic changes. Biomedicine and Pharmacotherapy. 2017;85:28-40
  5. 5. Keyhanmanesh R, Rahbarghazi R, Ahmadi M. Systemic transplantation of mesenchymal stem cells modulates endothelial cell adhesion molecules induced by ovalbumin in rat model of asthma. Inflammation. 2018:1-10
  6. 6. Keyhanmanesh R, Rahbarghazi R, Aslani MR, Hassanpour M, Ahmadi M. Systemic delivery of mesenchymal stem cells condition media in repeated doses acts as magic bullets in restoring IFN-γ/IL-4 balance in asthmatic rats. Life Sciences. 2018;212:30-36. DOI: 10.1016/j.lfs.2018.09.049
  7. 7. Zhao JJ, Liu JL, Liu L, Jia HY. Protection of mesenchymal stem cells on acute kidney injury. Molecular Medicine Reports. 2014;9(1):91-96
  8. 8. Chen Y, Xiang LX, Shao JZ, Pan RL, Wang YX, Dong XJ, et al. Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver. Journal of Cellular and Molecular Medicine. 2010;14(6b):1494-1508
  9. 9. Roubelakis MG, Tsaknakis G, Pappa KI, Anagnou NP, Watt SM. Spindle shaped human mesenchymal stem/stromal cells from amniotic fluid promote neovascularization. PLoS ONE. 2013;8(1):e54747-e. DOI: 10.1371/journal.pone.0054747
  10. 10. Pankajakshan D, Agrawal DK. Mesenchymal stem cell paracrine factors in vascular repair and regeneration. Journal of Biomedical Technology and Research. 2014;1(1). DOI: 10.19104/jbtr.2014.107
  11. 11. Bradshaw WJ, Rehman S, Pham TT, Thiyagarajan N, Lee RL, Subramanian V, et al. Structural insights into human angiogenin variants implicated in Parkinson’s disease and amyotrophic lateral sclerosis. Scientific Reports. 2017;7:41996
  12. 12. Souma T, Thomson BR, Heinen S, Anna Carota I, Yamaguchi S, Onay T, et al. Context-dependent functions of angiopoietin 2 are determined by the endothelial phosphatase VEPTP. Proceedings of the National Academy of Sciences. 2018;115(6):1298. DOI: 10.1073/pnas.1714446115
  13. 13. Yan Z-X, Luo Y, Liu N-F. Blockade of angiopoietin-2/Tie2 signaling pathway specifically promotes inflammation-induced angiogenesis in mouse cornea. International Journal of Ophthalmology. 2017;10(8):1187-1194. DOI: 10.18240/ijo.2017.08.01
  14. 14. Nassiri SM, Rahbarghazi R. Interactions of mesenchymal stem cells with endothelial cells. Stem Cells and Development. 2013;23(4):319-332
  15. 15. Chittiboina P, Ganta V, Monceaux CP, Scott LK, Nanda A, Alexander JS. Angiopoietins as promising biomarkers and potential therapeutic targets in brain injury. Pathophysiology. 2013;20(1):15-21
  16. 16. Wang C-Q , Huang Y-W, Wang S-W, Huang Y-L, Tsai C-H, Zhao Y-M, et al. Amphiregulin enhances VEGF-A production in human chondrosarcoma cells and promotes angiogenesis by inhibiting miR-206 via FAK/c-Src/PKCδ pathway. Cancer Letters. 2017;385:261-270. DOI: 10.1016/j.canlet.2016.10.010
  17. 17. Fielder GC, Yang TW-S, Razdan M, Li Y, Lu J, Perry JK, et al. The GDNF family: A role in cancer? Neoplasia (New York, NY). 2017;20(1):99-117. DOI: 10.1016/j.neo.2017.10.010
  18. 18. van den Hengel LG, Versteeg HH. Tissue factor signaling: A multi-faceted function in biological processes. Frontiers in Bioscience. 2011;3:1500-1510
  19. 19. Kumara HS, Pettke E, Shah A, Yan X, Cekic V, Downing MA, et al. Plasma levels of the proangiogenic protein CXCL16 remains elevated for 1 month after minimally invasive colorectal cancer resection. World Journal of Surgical Oncology. 2018;16(1):132
  20. 20. Wesley UV, Hatcher JF, Ayvaci ER, Klemp A, Dempsey RJ. Regulation of dipeptidyl peptidase IV in the post-stroke rat brain and in vitro ischemia: Implications for chemokine-mediated neural progenitor cell migration and angiogenesis. Molecular Neurobiology. 2017;54(7):4973-4985. DOI: 10.1007/s12035-016-0039-4
  21. 21. Kim D, Dai J, Park Y-H, Fai LY, Wang L, Pratheeshkumar P, et al. Activation of epidermal growth factor receptor/p38/hypoxia-inducible factor-1α is pivotal for angiogenesis and tumorigenesis of malignantly transformed cells induced by hexavalent chromium. Journal of Biological Chemistry. 2016;291(31):16271-16281. DOI: 10.1074/jbc.M116.715797
  22. 22. Traboulsi W, Sergent F, Boufettal H, Brouillet S, Slim R, Hoffmann P, et al. Antagonism of EG-VEGF receptors as targeted therapy for choriocarcinoma progression in vitro and in vivo. Clinical Cancer Research. 2017;23:7130-7140. DOI: 10.1158/1078-0432.CCR-17-0811
  23. 23. Zheng W, Aspelund A, Alitalo K. Lymphangiogenic factors, mechanisms, and applications. The Journal of Clinical Investigation. 2014;124(3):878-887
  24. 24. Núñez-Gómez E, Pericacho M, Ollauri-Ibáñez C, Bernabéu C, López-Novoa JM. The role of endoglin in post-ischemic revascularization. Angiogenesis. 2017;20(1):1-24
  25. 25. Xu Y, Zhu W, Wang T, Jin L, Liu T, Li X, et al. Low molecule weight fucoidan mitigates atherosclerosis in ApoE (-/-) mouse model through activating multiple signal pathway. Carbohydrate Polymers. 2019;206:110-120
  26. 26. McDonnell N, Evans RM, Downes M. Methods of treating lipodystrophy using fgf-1 compounds. In: Google Patents. 2018
  27. 27. Hosaka K, Yang Y, Nakamura M, Andersson P, Yang X, Zhang Y, et al. Dual roles of endothelial FGF-2–FGFR1–PDGF-BB and perivascular FGF-2–FGFR2–PDGFRβ signaling pathways in tumor vascular remodeling. Cell Discovery. 2018;4(1):3
  28. 28. Kook S-H, Jeon Y-M, Lim S-S, Jang M-J, Cho E-S, Lee S-Y, et al. Fibroblast growth factor-4 enhances proliferation of mouse embryonic stem cells via activation of c-Jun signaling. PLoS ONE. 2013;8(8):e71641. DOI: 10.1371/journal.pone.0071641
  29. 29. Chen M, Ba H, Lu C, Dai J, Sun J. Glial cell line-derived neurotrophic factor (GDNF) promotes angiogenesis through the demethylation of the fibromodulin (FMOD) promoter in glioblastoma. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2018;24:6137
  30. 30. Ribatti D, Tamma R. Hematopoietic growth factors and tumor angiogenesis. Cancer Letters. 2019;440-441:47-53. DOI: 10.1016/j.canlet.2018.10.008
  31. 31. Dredge K, Hammond E, Handley P, Gonda T, Smith M, Vincent C, et al. PG545, a dual heparanase and angiogenesis inhibitor, induces potent anti-tumour and anti-metastatic efficacy in preclinical models. British Journal of Cancer. 2011;104(4):635
  32. 32. Li Z, Yan H, Yuan J, Cao L, Lin A, Dai H, et al. Pharmacological inhibition of heparin-binding EGF-like growth factor promotes peritoneal angiogenesis in a peritoneal dialysis rat model. Clinical and Experimental Nephrology. 2018;22(2):257-265
  33. 33. Van de Kamp J, Paefgen V, Wöltje M, Böbel M, Jaekel J, Rath B, et al. Mesenchymal stem cells can be recruited to wounded tissue via hepatocyte growth factor-loaded biomaterials. Journal of Tissue Engineering and Regenerative Medicine. 2017;11(11):2988-2998
  34. 34. Wang C-G, Lou Y-T, Tong M-J, Zhang L-L, Zhang Z-J, Feng Y-Z, et al. Asperosaponin VI promotes angiogenesis and accelerates wound healing in rats via up-regulating HIF-1α/VEGF signaling. Acta Pharmacologica Sinica. 2018;39(3):393
  35. 35. Syed SN, Jung M, Weigert A, Brüne B. S1P provokes tumor lymphangiogenesis via macrophage-derived mediators such as IL-1β or lipocalin-2. Mediators of Inflammation. 2017;2017
  36. 36. Tang R, Zhang G, Chen S-Y. Smooth muscle cell proangiogenic phenotype induced by cyclopentenyl cytosine promotes endothelial cell proliferation and migration. The Journal of Biological Chemistry. 2016;291(52):26913-26921. DOI: 10.1074/jbc.M116.741967
  37. 37. Shi J, Wei P-K. Interleukin-8: A potent promoter of angiogenesis in gastric cancer. Oncology Letters. 2016;11(2):1043-1050. DOI: 10.3892/ol.2015.4035
  38. 38. Hubert A, Bochenek ML, Schütz E, Gogiraju R, Münzel T, Schäfer K. Selective deletion of leptin signaling in endothelial cells enhances neointima formation and phenocopies the vascular effects of diet-induced obesity in mice. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017 ATVBAHA.117.309798
  39. 39. Chen L, Liu G-Q , Wu H-Y, Jin J, Yin X, Li D, et al. Monocyte chemoattractant protein 1 and fractalkine play opposite roles in angiogenesis via recruitment of different macrophage subtypes. International Journal of Ophthalmology. 2018;11(2):216
  40. 40. Fang C, Wen G, Zhang L, Lin L, Moore A, Wu S, et al. An important role of matrix metalloproteinase-8 in angiogenesis in vitro and in vivo. Cardiovascular Research. 2013;99(1):146-155
  41. 41. Nielsen SH, Flynn E, Lindsey M, editors. Macrophage-derived osteopontin is fragmented by MMP-9 to hinder angiogenesis in the post-myocardial infarction left ventricle. In: ESC Congress 2017. 2017
  42. 42. Lok J, Sardi SP, Guo S, Besancon E, Ha DM, Rosell A, et al. Neuregulin-1 signaling in brain endothelial cells. Journal of Cerebral Blood Flow and Metabolism. 2009;29(1):39-43. DOI: 10.1038/jcbfm.2008.94
  43. 43. Rajkovic I, Wong R, Lemarchand E, Rivers-Auty J, Rajkovic O, Garlanda C, et al. Pentraxin 3 promotes long-term cerebral blood flow recovery, angiogenesis, and neuronal survival after stroke. Journal of Molecular Medicine (Berlin, Germany). 2018;96(12):1319-1332. DOI: 10.1007/s00109-018-1698-6
  44. 44. Liu W, Zhang J, Yao X, Jiang C, Ni P, Cheng L, et al. Bevacizumab-enhanced antitumor effect of 5-fluorouracil via upregulation of thymidine phosphorylase through vascular endothelial growth factor A/vascular endothelial growth factor receptor 2-specificity protein 1 pathway. Cancer Science. 2018;109(10):3294
  45. 45. Gianni-Barrera R, Butschkau A, Uccelli A, Certelli A, Valente P, Bartolomeo M, et al. PDGF-BB regulates splitting angiogenesis in skeletal muscle by limiting VEGF-induced endothelial proliferation. Angiogenesis. 2018;21(4):883-900
  46. 46. Pang V, Bates DO, Leach L. Regulation of human feto-placental endothelial barrier integrity by vascular endothelial growth factors: Competitive interplay between VEGF-A165a, VEGF-A165b, PIGF and VE-cadherin. Clinical Science. 2017. CS20171252
  47. 47. Nakajima R, Nakamura E, Harigaya T. Vasoinhibin, an n-terminal prolactin fragment, directly inhibits cardiac angiogenesis in three-dimensional heart culture. Frontiers in Endocrinology. 2017;8:4
  48. 48. Dai L, Liu Y, Xie L, Wu X, Qiu L, Di W. Sphingosine kinase 1/sphingosine-1-phosphate (S1P)/S1P receptor axis is involved in ovarian cancer angiogenesis. Oncotarget. 2017;8(43):74947
  49. 49. Ma Y-L, Li W-D, Lei F-R, Qian A-M, Zhu L-W, Jiang K, et al. Metformin inhibits angiogenesis in endothelial progenitor cells through inhibiting MMP2, MMP9 and uPA expression via AMPK-mTOR-autophagy pathway. International Journal of Clinical and Experimental Medicine. 2017;10(1):958-964
  50. 50. Rahbarghazi R, Nassiri SM, Ahmadi SH, Mohammadi E, Rabbani S, Araghi A, et al. Dynamic induction of pro-angiogenic milieu after transplantation of marrow-derived mesenchymal stem cells in experimental myocardial infarction. International Journal of Cardiology. 2014;173(3):453-466. DOI: 10.1016/j.ijcard.2014.03.008
  51. 51. Shen C, Lie P, Miao T, Yu M, Lu Q , Feng T, et al. Conditioned medium from umbilical cord mesenchymal stem cells induces migration and angiogenesis. Molecular Medicine Reports. 2015;12(1):20-30
  52. 52. Bussche L, Van de Walle GR. Peripheral blood-derived mesenchymal stromal cells promote angiogenesis via paracrine stimulation of vascular endothelial growth factor secretion in the equine model. Stem Cells Translational Medicine. 2014;3(12):1514-1525
  53. 53. Kwon HM, Hur S-M, Park K-Y, Kim C-K, Kim Y-M, Kim H-S, et al. Multiple paracrine factors secreted by mesenchymal stem cells contribute to angiogenesis. Vascular Pharmacology. 2014;63(1):19-28
  54. 54. Chen J-X, Zeng H, Reese J, Aschner JL, Meyrick B. Overexpression of angiopoietin-2 impairs myocardial angiogenesis and exacerbates cardiac fibrosis in the diabetic db/db mouse model. American Journal of Physiology: Heart and Circulatory Physiology. 2012;302(4):H1003-H1H12. DOI: 10.1152/ajpheart.00866.2011
  55. 55. Yun J, Park S, Kim J, Park Y, Cho C. Angiopoietin 2 induces astrocyte apoptosis via αvβ5-integrin signaling in diabetic retinopathy. Cell Death & Disease. 2017;7(2):e2101
  56. 56. Sivaraman Siveen K, Prabhu K, Krishnankutty R, Kuttikrishnan S, Tsakou M, Q Alali F, et al. Vascular endothelial growth factor (VEGF) signaling in tumour vascularization: Potential and challenges. Current Vascular Pharmacology. 2017;15(4):339-351
  57. 57. Sui H, Zhao J, Zhou L, Wen H, Deng W, Li C, et al. Tanshinone IIA inhibits β-catenin/VEGF-mediated angiogenesis by targeting TGF-β1 in normoxic and HIF-1α in hypoxic microenvironments in human colorectal cancer. Cancer Letters. 2017;403:86-97
  58. 58. Jian J, Pang Y, Yan HH, Min Y, Achyut BR, Hollander MC, et al. Platelet factor 4 is produced by subsets of myeloid cells in premetastatic lung and inhibits tumor metastasis. Oncotarget. 2017;8(17):27725
  59. 59. Chang I-W, Liu K-W, Ragunanan M, He H-L, Shiue Y-L, Yu S-C. SERPINB5 expression: Association with CCRT response and prognostic value in rectal cancer. International Journal of Medical Sciences. 2018;15(4):376
  60. 60. Meidan R, Girsh E, Mamluk R, Levy N, Farberov S. Luteolysis in ruminants: Past concepts, new insights, and persisting challenges. In: The Life Cycle of the Corpus Luteum. Springer; 2017. pp. 159-182
  61. 61. Baxter-Holland M, Dass CR. Pigment epithelium-derived factor: A key mediator in bone homeostasis and potential for bone regenerative therapy. Journal of Pharmacy and Pharmacology. 2018;70(9):1127-1138
  62. 62. Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: Versatile extracellular regulators in cancer. Nature Reviews Cancer. 2017;17(1):38
  63. 63. Sandrim VC, Diniz S, Eleuterio NM, Gomes KB, Dusse LMS, Cavalli RC. Higher levels of circulating TIMP-4 in preeclampsia is strongly associated with clinical parameters and microRNA. Clinical and Experimental Hypertension. 2018;40(7):609-612
  64. 64. Samuel SM, Ghosh S, Majeed Y, Ding H, Triggle CR. Anti-angiogenic effects of metformin in 2-deoxyglucose treated microvascular endothelial cells: Role of thrombospondin-1. The FASEB Journal. 2017;31(1 Supplement):824.5
  65. 65. Nova-Lampeti E, Aguilera V, Oporto K, Guzmán P, Ormazábal V, Zúñiga F, et al. Hox genes in adult tissues and their role in endothelial cell differentiation and angiogenesis. In: Endothelial Dysfunction—Old Concepts and New Challenges. IntechOpen; 2018
  66. 66. Nakagawa S, Okabe H, Ouchi M, Tokunaga R, Umezaki N, Higashi T, et al. Enhancer of zeste homolog 2 (EZH2) regulates tumor angiogenesis and predicts recurrence and prognosis of intrahepatic cholangiocarcinoma. HPB. 2018
  67. 67. Liu J, Hao H, Xia L, Ti D, Huang H, Dong L, et al. Hypoxia pretreatment of bone marrow mesenchymal stem cells facilitates angiogenesis by improving the function of endothelial cells in diabetic rats with lower ischemia. PLoS ONE. 2015;10(5):e0126715. DOI: 10.1371/journal.pone.0126715
  68. 68. Lobov IB, Brooks PC, Lang RA. Angiopoietin-2 displays VEGF-dependent modulation of capillary structure and endothelial cell survival in vivo. Proceedings of the National Academy of Sciences of the United States of America. 2002;99(17):11205-11210. DOI: 10.1073/pnas.172161899
  69. 69. Zavala G, Prieto CP, Villanueva AA, Palma V. Sonic hedgehog (SHH) signaling improves the angiogenic potential of Wharton's jelly-derived mesenchymal stem cells (WJ-MSC). Stem Cell Research & Therapy. 2017;8(1):203. DOI: 10.1186/s13287-017-0653-8
  70. 70. Matluobi D, Araghi A, Maragheh BFA, Rezabakhsh A, Soltani S, Khaksar M, et al. Carvacrol promotes angiogenic paracrine potential and endothelial differentiation of human mesenchymal stem cells at low concentrations. Microvascular Research. 2018;115:20-27
  71. 71. Mandò C, Razini P, Novielli C, Anelli GM, Belicchi M, Erratico S, et al. Impaired angiogenic potential of human placental mesenchymal stromal cells in intrauterine growth restriction. Stem Cells Translational Medicine. 2016;5(4):451-463. DOI: 10.5966/sctm.2015-0155
  72. 72. Zhang S, Pan C, Lv X, Wu W, Chen H, Wu W, et al. Repression of Abd-B by polycomb is critical for cell identity maintenance in adult Drosophila testis. Scientific Reports. 2017;7(1):5101. DOI: 10.1038/s41598-017-05359-0
  73. 73. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal stem cell secretome: Toward cell-free therapeutic strategies in regenerative medicine. International Journal of Molecular Sciences. 2017;18(9):1852. DOI: 10.3390/ijms18091852
  74. 74. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba'aqeel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? American Journal of Obstetrics and Gynecology. 2006;194(4):921-931
  75. 75. Rezaie J, Mehranjani MS, Rahbarghazi R, Shariatzadeh MA. Angiogenic and restorative abilities of human mesenchymal stem cells were reduced following treatment with serum from diabetes mellitus type 2 patients. Journal of Cellular Biochemistry. 2018;119(1):524-535
  76. 76. Torán JL, Aguilar S, López JA, Torroja C, Quintana JA, Santiago C, et al. CXCL6 is an important paracrine factor in the pro-angiogenic human cardiac progenitor-like cell secretome. Scientific Reports. 2017;7(1):12490. DOI: 10.1038/s41598-017-11976-6
  77. 77. Nemati S, Rezabakhsh A, Khoshfetrat AB, Nourazarian A, Biray Avci Ç, Goker Bagca B, et al. Alginate-gelatin encapsulation of human endothelial cells promoted angiogenesis in in vivo and in vitro milieu. Biotechnology and Bioengineering. 2017;114(12):2920-2930
  78. 78. Katare R, Riu F, Rowlinson J, Lewis A, Holden R, Meloni M, et al. Perivascular delivery of encapsulated mesenchymal stem cells improves postischemic angiogenesis via paracrine activation of VEGF-A significance. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013;33(8):1872-1880
  79. 79. Costa MH, McDevitt TC, Cabral JM, da Silva CL, Ferreira FC. Tridimensional configurations of human mesenchymal stem/stromal cells to enhance cell paracrine potential towards wound healing processes. Journal of Biotechnology. 2017;262:28-39
  80. 80. Corrado C, Raimondo S, Chiesi A, Ciccia F, De Leo G, Alessandro R. Exosomes as intercellular signaling organelles involved in health and disease: Basic science and clinical applications. International Journal of Molecular Sciences. 2013;14(3):5338-5366
  81. 81. Rezaie J, Ajezi S, Avci ÇB, Karimipour M, Geranmayeh MH, Nourazarian A, et al. Exosomes and their application in biomedical field: Difficulties and advantages. Molecular Neurobiology. 2018;55(4):3372-3393
  82. 82. Hassanpour M, Cheraghi O, Brazvan B, Hiradfar A, Aghamohammadzadeh N, Rahbarghazi R, et al. Chronic exposure of human endothelial progenitor cells to diabetic condition abolished the regulated kinetics activity of exosomes. Iranian Journal of Pharmaceutical Research. 2018;17(3):1068
  83. 83. Théry C, Zitvogel L, Amigorena S. Exosomes: Composition, biogenesis and function. Nature Reviews Immunology. 2002;2(8):569
  84. 84. Rezaie J, Nejati V, Khaksar M, Oryan A, Aghamohamadzadeh N, Shariatzadeh MA, et al. Diabetic sera disrupted the normal exosome signaling pathway in human mesenchymal stem cells in vitro. Cell and Tissue Research. 2018:1-11
  85. 85. Kowal J, Tkach M, Théry C. Biogenesis and secretion of exosomes. Current Opinion in Cell Biology. 2014;29:116-125
  86. 86. Colombo M, Moita C, van Niel G, Kowal J, Vigneron J, Benaroch P, et al. Analysis of ESCRT functions in exosome biogenesis, composition and secretion highlights the heterogeneity of extracellular vesicles. Journal of Cell Science. DOI: 10.1242/jcs.128868
  87. 87. Trajkovic K, Hsu C, Chiantia S, Rajendran L, Wenzel D, Wieland F, et al. Ceramide triggers budding of exosome vesicles into multivesicular endosomes. Science. 2008;319(5867):1244-1247
  88. 88. Robbins PD, Morelli AE. Regulation of immune responses by extracellular vesicles. Nature Reviews Immunology. 2014;14(3):195
  89. 89. Aoki N, Yokoyama R, Asai N, Ohki M, Ohki Y, Kusubata K, et al. Adipocyte-derived microvesicles are associated with multiple angiogenic factors and induce angiogenesis in vivo and in vitro. Endocrinology. 2010;151(6):2567-2576
  90. 90. Wang L, Zhao Y, Shi S. Interplay between mesenchymal stem cells and lymphocytes: Implications for immunotherapy and tissue regeneration. Journal of Dental Research. 2012;91(11):1003-1010
  91. 91. Lee J-K, Park S-R, Jung B-K, Jeon Y-K, Lee Y-S, Kim M-K, et al. Exosomes derived from mesenchymal stem cells suppress angiogenesis by down-regulating VEGF expression in breast cancer cells. PLoS ONE. 2013;8(12):e84256
  92. 92. Teng X, Chen L, Chen W, Yang J, Yang Z, Shen Z. Mesenchymal stem cell-derived exosomes improve the microenvironment of infarcted myocardium contributing to angiogenesis and anti-inflammation. Cellular Physiology and Biochemistry. 2015;37(6):2415-2424
  93. 93. Anderson JD, Johansson HJ, Graham CS, Vesterlund M, Pham MT, Bramlett CS, et al. Comprehensive proteomic analysis of mesenchymal stem cell exosomes reveals modulation of angiogenesis via nuclear factor-kappaB signaling. Stem Cells. 2016;34(3):601-613
  94. 94. Gong M, Yu B, Wang J, Wang Y, Liu M, Paul C, et al. Mesenchymal stem cells release exosomes that transfer miRNAs to endothelial cells and promote angiogenesis. Oncotarget. 2017;8(28):45200
  95. 95. Liang X, Zhang L, Wang S, Han Q , Zhao RC. Exosomes secreted by mesenchymal stem cells promote endothelial cell angiogenesis by transferring miR-125a. Journal of Cell Science. 2016;129(11):2182-2189
  96. 96. Svensson KJ, Kucharzewska P, Christianson HC, Sköld S, Löfstedt T, Johansson MC, et al. Hypoxia triggers a proangiogenic pathway involving cancer cell microvesicles and PAR-2-mediated heparin-binding EGF signaling in endothelial cells. Proceedings of the National Academy of Sciences. 2011;108(32):13147-13152
  97. 97. Bian S, Zhang L, Duan L, Wang X, Min Y, Yu H. Extracellular vesicles derived from human bone marrow mesenchymal stem cells promote angiogenesis in a rat myocardial infarction model. Journal of Molecular Medicine. 2014;92(4):387-397
  98. 98. Chen Z, Wang H, Xia Y, Yan F, Lu Y. Therapeutic potential of mesenchymal cell-derived miRNA-150-5p-expressing exosomes in rheumatoid arthritis mediated by the modulation of MMP14 and VEGF. The Journal of Immunology. 2018;201(8):2472-2482
  99. 99. Shabbir A, Cox A, Rodriguez-Menocal L, Salgado M, Badiavas EV. Mesenchymal stem cell exosomes induce proliferation and migration of normal and chronic wound fibroblasts, and enhance angiogenesis in vitro. Stem Cells and Development. 2015;24(14):1635-1647
  100. 100. Zou X, Gu D, Xing X, Cheng Z, Gong D, Zhang G, et al. Human mesenchymal stromal cell-derived extracellular vesicles alleviate renal ischemic reperfusion injury and enhance angiogenesis in rats. American Journal of Translational Research. 2016;8(10):4289
  101. 101. Zhang J, Guan J, Niu X, Hu G, Guo S, Li Q , et al. Exosomes released from human induced pluripotent stem cells-derived MSCs facilitate cutaneous wound healing by promoting collagen synthesis and angiogenesis. Journal of Translational Medicine. 2015;13(1):49
  102. 102. Lai RC, Arslan F, Lee MM, Sze NSK, Choo A, Chen TS, et al. Exosome secreted by MSC reduces myocardial ischemia/reperfusion injury. Stem Cell Research. 2010;4(3):214-222
  103. 103. Camussi G, Deregibus MC, Tetta C. Paracrine/endocrine mechanism of stem cells on kidney repair: Role of microvesicle-mediated transfer of genetic information. Current Opinion in Nephrology and Hypertension. 2010;19(1):7-12
  104. 104. Quesenberry PJ, Dooner MS, Aliotta JM. Stem cell plasticity revisited: The continuum marrow model and phenotypic changes mediated by microvesicles. Experimental Hematology. 2010;38(7):581-592
  105. 105. Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, et al. Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Letters. 2012;315(1):28-37
  106. 106. López-Cobo S, Campos-Silva C, Moyano A, Oliveira-Rodríguez M, Paschen A, Yáñez-Mó M, et al. Immunoassays for scarce tumour-antigens in exosomes: Detection of the human NKG2D-ligand, MICA, in tetraspanin-containing nanovesicles from melanoma. Journal of Nanobiotechnology. 2018;16(1):47
  107. 107. Xue C, Shen Y, Li X, Li B, Zhao S, Gu J, et al. Exosomes derived from hypoxia-treated human adipose mesenchymal stem cells enhance angiogenesis through the PKA signaling pathway. Stem Cells and Development. 2018;27(7):456-465
  108. 108. Yu B, Gong M, Wang Y, Millard RW, Pasha Z, Yang Y, et al. Cardiomyocyte protection by GATA-4 gene engineered mesenchymal stem cells is partially mediated by translocation of miR-221 in microvesicles. PLoS ONE. 2013;8(8):e73304
  109. 109. Keshtkar S, Azarpira N, Ghahremani MH. Mesenchymal stem cell-derived extracellular vesicles: Novel frontiers in regenerative medicine. Stem Cell Research & Therapy. 2018;9(1):63
  110. 110. Zhou J, Tan X, Tan Y, Li Q , Ma J, Wang G. Mesenchymal stem cell derived exosomes in cancer progression, metastasis and drug delivery: A comprehensive review. Journal of Cancer. 2018;9(17):3129
  111. 111. Goodarzi P, Larijani B, Alavi-Moghadam S, Tayanloo-Beik A, Mohamadi-Jahani F, Ranjbaran N et al. Mesenchymal Stem Cells-Derived Exosomes for Wound Regeneration. 2018
  112. 112. Rani S, Ritter T. The Exosome—A Naturally Secreted Nanoparticle and its Application to Wound Healing. Advanced Materials. 2016;28(27):5542-5552
  113. 113. Zhang B, Wang M, Gong A, Zhang X, Wu X, Zhu Y, et al. HucMSC-exosome mediated-Wnt4 signaling is required for cutaneous wound healing. Stem Cells. 2015;33(7):2158-2168
  114. 114. Yuan Y, Du W, Liu J, Ma W, Zhang L, Du Z, et al. Stem cell-derived exosome in cardiovascular diseases: Macro roles of micro particles. Frontiers in Pharmacology. 2018;9
  115. 115. Sharma A. Role of stem cell derived exosomes in tumor biology. International Journal of Cancer. 2018;142(6):1086-1092
  116. 116. Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD. Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie. 2013;95(12):2235-2245. DOI: 10.1016/j.biochi.2013.05.010
  117. 117. Jeevanantham V, Butler M, Saad A, Abdel-Latif A, Zuba-Surma EK, Dawn B. Adult bone marrow cell therapy improves survival and induces long-term improvement in cardiac parameters: A systematic review and meta-analysis. Circulation. 2012 CIRCULATIONAHA.111.086074
  118. 118. Jeevanantham V, Afzal MR, Zuba-Surma EK, Dawn B. Clinical trials of cardiac repair with adult bone marrow-derived cells. Cellular Cardiomyoplasty. 2013:179-205
  119. 119. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, et al. Intracoronary bone marrow–derived progenitor cells in acute myocardial infarction. New England Journal of Medicine. 2006;355(12):1210-1221
  120. 120. Arslan F, Lai RC, Smeets MB, Akeroyd L, Choo A, Aguor EN, et al. Mesenchymal stem cell-derived exosomes increase ATP levels, decrease oxidative stress and activate PI3K/Akt pathway to enhance myocardial viability and prevent adverse remodeling after myocardial ischemia/reperfusion injury. Stem Cell Research. 2013;10(3):301-312
  121. 121. Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: A detailed progress report of the last 6 years (2010-2015). Stem Cell Research & Therapy. 2016;7(1):82. DOI: 10.1186/s13287-016-0341-0
  122. 122. Hodgkinson CP, Bareja A, Gomez JA, Dzau VJ. Emerging concepts in paracrine mechanisms in regenerative cardiovascular medicine and biology. Circulation Research. 2016;118(1):95-107
  123. 123. Huang L, Ma W, Ma Y, Feng D, Chen H, Cai B. Exosomes in mesenchymal stem cells, a new therapeutic strategy for cardiovascular diseases? International Journal of Biological Sciences. 2015;11(2):238
  124. 124. Caporali A, Bäck M, Daemen MJ, Hoefer IE, Jones EA, Lutgens E, et al. Future directions for therapeutic strategies in post-ischaemic vascularization: A position paper from European Society of Cardiology Working Group on Atherosclerosis and Vascular Biology. Cardiovascular Research. 2018;114(11):1411-1421
  125. 125. Lou G, Chen Z, Zheng M, Liu Y. Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases. Experimental & Molecular Medicine. 2017;49(6):e346-e34e. DOI: 10.1038/emm.2017.63
  126. 126. Yong KW, Choi JR, Mohammadi M, Mitha AP, Sanati-Nezhad A, Sen A. Mesenchymal stem cell therapy for ischemic tissues. Stem Cells International. 2018;2018:8179075. DOI: 10.1155/2018/8179075
  127. 127. Tao H, Han Z, Han ZC, Li Z. Proangiogenic features of mesenchymal stem cells and their therapeutic applications. Stem Cells International. 2016;2016
  128. 128. Kir D, Schnettler E, Modi S, Ramakrishnan S. Regulation of angiogenesis by microRNAs in cardiovascular diseases. Angiogenesis. 2018:1-12
  129. 129. Lemcke H, Voronina N, Steinhoff G, David R. Recent progress in stem cell modification for cardiac regeneration. Stem Cells International. 2018;2018
  130. 130. Rahbarghazi R, Nassiri SM, Khazraiinia P, Kajbafzadeh A-M, Ahmadi SH, Mohammadi E, et al. Juxtacrine and paracrine interactions of rat marrow-derived mesenchymal stem cells, muscle-derived satellite cells, and neonatal cardiomyocytes with endothelial cells in angiogenesis dynamics. Stem Cells and Development. 2012;22(6):855-865
  131. 131. Rezabakhsh A, Nabat E, Yousefi M, Montazersaheb S, Cheraghi O, Mehdizadeh A, et al. Endothelial cells’ biophysical, biochemical, and chromosomal aberrancies in high-glucose condition within the diabetic range. Cell Biochemistry and Function. 2017;35(2):83-97
  132. 132. Kruger EA, Duray PH, Tsokos MG, Venzon DJ, Libutti SK, Dixon SC, et al. Endostatin inhibits microvessel formation in the ex vivo rat aortic ring angiogenesis assay. Biochemical and Biophysical Research Communications. 2000;268(1):183-191
  133. 133. Grogan JA, Connor AJ, Pitt-Francis JM, Maini PK, Byrne HM. The importance of geometry in the corneal micropocket angiogenesis assay. PLoS Computational Biology. 2018;14(3):e1006049

Written By

Jafar Rezaie, Morteza Heidarzadeh, Mehdi Hassanpour, Hassan Amini, Elhameh Shokrollahi, Mahdi Ahmadi and Reza Rahbarghazi

Submitted: 20 November 2018 Reviewed: 15 January 2019 Published: 23 September 2019